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WO2022233398A1 - Composés pour réduire la lipoprotéine (a) - Google Patents

Composés pour réduire la lipoprotéine (a) Download PDF

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Publication number
WO2022233398A1
WO2022233398A1 PCT/EP2021/061679 EP2021061679W WO2022233398A1 WO 2022233398 A1 WO2022233398 A1 WO 2022233398A1 EP 2021061679 W EP2021061679 W EP 2021061679W WO 2022233398 A1 WO2022233398 A1 WO 2022233398A1
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Prior art keywords
tetrahydroxy
acid
compound
cholan
oic acid
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Gerhard Kostner
Nahid KOSTNER
Karam KOSTNER
Bernd KOSTNER
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Kostner Pharma GmbH
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Kostner Pharma GmbH
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Priority to PCT/EP2021/061679 priority Critical patent/WO2022233398A1/fr
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Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the use of polyhydroxylated bile acid compounds in the treatment of a subject suffering from an increased plasma level of lipoprotein (a).
  • Cholesterol is a ubiquitous biological substance produced in numerous human organs and cells. It has important physiological functions such as stabilization of cell membranes, precursor of bile acids and steroid hormones. On the other hand, any excess of cholesterol is deleterious and causes numerous diseases among them coronary heart disease, myocardial infarction and stroke. [0003] Cholesterol is transported in blood in several lipoproteins: Very-low-, low-, and high-density lipoproteins (VLDL, LDL, and HDL). Whereas HDL is considered to be beneficial, excess VLDL and LDL are detrimental. There are several medications available to treat subjects with elevated LDL- and VLDL-cholesterol efficiently.
  • VLDL Very-low-, low-, and high-density lipoproteins
  • Lp(a) lipoprotein(a)
  • Lp(a) is considered to be even more atherogenic than LDL or VLDL.
  • Lp(a) consists of an LDL-like core particle plus the characteristic antigen, Apo(a), a large glycoprotein with a molecular mass of about 500 kD.
  • Apo(a) the characteristic antigen
  • the liver is the central organ for the biosynthesis of all lipoproteins.
  • Lp(a) is almost exclusively produced there.
  • It is generally acknowledged that high plasma levels of Lp(a) are causally related to myocardial infarction and stroke. The plasma concentration of Lp(a) is highly skewed and great differences among various ethnic groups have been observed.
  • the conventional cholesterol lowering medications such as statins, bile acid sequestrants, or fibrates have little if any effect on plasma Lp(a) concentrations and may even lead to increased Lp(a) levels.
  • PCSK9 inhibitors relatively new drugs for lowering LDL-C may reduce Lp(a) up to 25%, but there are great inter-individual differences (Kostner, K.M., et a I., 2013. European Heart Journal, 34: 3268-3276). Nicotinic acid at higher doses may reduce Lp(a) levels up to 30% - yet this drug has been taken from the market in many countries because of unwanted side effects (Chennamsetty I. et a I., (2012) J. Lipid Res. 53: 2405-2412).
  • Lp(a) is biosynthesized in the liver.
  • Lp(a) plasma concentration is primarily determined by the rate of Apo(a) biosynthesis whereas the catabolic rate of Lp(a) has little impact.
  • an effective medication should interfere with the synthesis rate of Apo(a).
  • FXR Farnesoid-X Receptor
  • Binding of ligands to FXR stimulates its transport to the nucleus and the interference with the binding of HNF4a, a positive transcription factor for Apo(a), to its response element and cessation of Apo(a) expression. Both mechanisms together lead to a blocking of Apo(a) transcription.
  • Very effective FXR agonists are bile acids, in humans cholic acid, chenodeoxycholic acid deoxy cholic acid and different conjugated forms thereof. These bile acids - in particular the lipophilic ones - may be toxic at higher concentrations and not suitable for long-term medications. Furthermore, there are numerous bile acids and derivatives thereof that have no impact on plasma Lp(a) levels at all.
  • ursodeoxycholic acid a compound used for the treatment of primary biliary cirrhosis.
  • W02009105897A1 and WO2011022838A1 disclose polyhydroxylated bile acids for the treatment of biliary disorders.
  • W02013041519A1 discloses compounds with a polyhydroxylated cholane skeleton for use as modulators of the retinoid-receptor related orphan receptor (ROR). Exemplified are different 1/3 ,3a,7a,12a-tetrahydroxy-5 3 -cholan-24-oate compounds. These compounds exhibited an improvement in insulin sensitivity in obese insulin resistant mice.
  • ROR retinoid-receptor related orphan receptor
  • the invention provides polyhydroxylated bile acids (PHBA) for the treatment of subjects with elevated Lp(a) levels.
  • PHBA polyhydroxylated bile acids
  • a polyhydroxylated bile acid compound or a pharmaceutically acceptable salt thereof for use in the treatment of a subject suffering from an increased plasma level of lipoprotein (a) (Lp(a)).
  • the plasma level of Lp(a) in said subject is above the concentration by consensus recommendations of about >30 mg/dl.
  • the plasma level of Lp(a) in said subject is decreased by at least 10% compared to the baseline value.
  • the polyhydroxylated bile acid compound is conjugated to a pharmaceutically acceptable moiety.
  • said pharmaceutically acceptable moiety is selected from the group consisting of amino sulfonic acid, an amine and amino acid.
  • said pharmaceutically acceptable moiety is selected from the group consisting of ethanolamine, taurine, glycine or serine.
  • the polyhydroxylated bile acid compound according to the invention is a tetrahydroxylated bile acid.
  • the tetrahydroxylated bile acid according to the invention is selected from the group consisting of
  • the tetrahydroxylated bile acid according to the invention is selected from the group consisting of
  • the polyhydroxylated bile acid according to the invention is 3a, 6a, 7a, 12a-tetra hydroxy-5 b -cholan-24-oic acid.
  • the increased plasma level of Lp(a) of the subject is the cause of an associated disease.
  • the associated disease is one of hyperlipidemia, dyslipidemia, atherosclerosis, hypertension, thrombosis, disorder of hemostasis, cardiovascular disease, aortic calcification, stroke, kidney disease or Type-ll diabetes.
  • the polyhydroxylated bile acid according to the invention is used in combination with a cholesterol lowering agent.
  • said cholesterol lowering agent is a cholesterol synthesis inhibitor or a cholesterol absorption inhibitor.
  • a pharmaceutical composition for use in the prevention or treatment of a disease associated with an increased Lp(a) plasma level in a subject comprising a polyhydroxylated bile acid compound according to the present invention and a pharmaceutical acceptable carrier.
  • said disease is one of hyperlipidemia, dyslipidemia, atherosclerosis, hypertension, thrombosis, disorder of hemostasis, cardiovascular disease, aortic calcification, stroke, kidney disease or Type-ll diabetes.
  • said disease is hyperlipidemia, dyslipidemia, hypertension, or Type-ll diabetes.
  • Fig.l Primary hepatocytes from tg-Apo(a) mice were incubated for 24h with 3a,6a,7a,12a-tetrahydroxy-5 b -cholan-24-oic acid and the expression of Apo(a) was measured by RT-PCR. Values on the y-axis are relative expressions in relation to the control hepatocytes without THBA. Results are mean ⁇ SEM of three independent experiments. (**P ⁇ 0.01***P ⁇ 0.001).
  • Fig. 2 Primary hepatocytes from tg-Apo(a) mice were incubated for 24h with 3a,6a,7a,12a-tetrahydroxy-5 b -cholan-24-oic acid and the expression of Cyp7al was measured by RT-PCR. Values on the y-axis are relative expressions in relation to the control hepatocytes without TPIBA. Results are mean ⁇ SEM of three independent experiments. (***P ⁇ 0.001).
  • Fig. 3 8 tg-Apo(a) mice were fed for 1 week with 0.1% 3a, 6a, 7a, 12a- tetrahydroxy-5 b -cholan-24-oic acid and the expression of Apo(a) and Cyp7al was measured by RT-PCR. Values on the y-axis are relative expressions in relation to the control animals fed with chow diet without TPIBA. The data are mean ⁇ SEM from duplicate analyses. (***P ⁇ 0.001).
  • Fig. 4 6 tg-Apo(a) mice were fed with 0.2% 3a,6a,7a,12a-tetrahydroxy- 5 b -cholan-24-oic acid for 1 week and the plasma concentration of Apo(a) was measured in duplicates by an ELISA from Mercodia ® . Values are in mg/dl of Apo(a).
  • Fig. 5 6 tg-Apo(a) mice were fed with 1% 3a,6a,7a,12a-tetrahydroxy-5 b - cholan-24-oic acid for 2 weeks and the plasma concentration of Apo(a) was measured in duplicates by an ELISA from Mercodia ® . Values are in mg/dl of Apo(a).
  • Bile acids are amphiphilic molecules with 24 carbon atoms and consist of a hydrophobic and a rigid steroid nucleus, to which hydrophilic hydroxyl groups and a flexible acidic aliphatic side chain are attached.
  • the steroidal core of BAs constitutes a saturated cyclopentanoperhydrophenanthrene skeleton consisting of three six-membered rings (A, B, and C) and one five-membered ring (D).
  • Cholanoic acid is the archetypal C24 bile acid skeleton from which all other C24 bile acids can be derived.
  • 5 a and 5 b the latter isomer is the most biologically relevant.
  • Most naturally occurring bile acids are characterized by hydroxyl groups in the A, B, and C ring of the cholane skeleton.
  • the bile acid nucleus is curved because the A and the B rings are in a cvs-fused configuration.
  • the BAs in lower vertebrates are known as allo-BAs. In this case, A and B rings are trans linked (5 a -stereochemistry).
  • C 24 BAs constitute a major part of the bile.
  • the BAs are facially amphipathic, i.e., they contain both hydrophobic (lipid soluble) and hydrophilic (polar) faces.
  • polyhydroxylated bile acids refers to at least 4 hydroxy substituents and up to the maximal hydroxylation level of the bile acid compound.
  • Polyhydroxylated bile acids include but are not limited to tetrahydroxylated, pentahydroxylated, hexahydroxylated bile acids, etc. According to one embodiment of the invention tetrahydroxylated bile acids are preferred.
  • the polyhydroxylated bile acid compound according to the present invention is selected from the group consisting of tetrahydroxylated bile acids (THBA).
  • the polyhydroxylated bile acid according to the present invention is selected from the group consisting of 3,6,7,12-tetrahydroxy- cholan-24-oic acid, 3,4,7,12-tetrahydroxy-cholan-24-oic acid, 1,3,7,12- tetrahydroxy-cholan-24-oic acid, 2,3,7,12-tetrahydroxy-cholan-24-oic acid, 2,4,7,12-cholan-24-oic acid, and 2,6,7,12-cholan-24-oic acid.
  • the polyhydroxylated bile acid according to the present invention is selected from the group consisting of 3a, 6a, 7a, 12a- tetrahydroxy-5/3 -cholan-24-oic acid, 3a, 6/3 ,7a,12a-tetrahydroxy-5 b -cholan-24- oic acid, 3a, 6a, 7 b ,12a-tetrahydroxy-5 b -cholan-24-oic acid, 3a, 6a, 7a, 12 b - tetrahydroxy-5 3 -cholan-24-oic acid, 3a, 6/3 ,7a, 12/3 -tetrahydroxy-5 b -cholan-24- oic acid, and 3a, 6/3 ,7 b ,12/3 -tetrahydroxy-5/3 -cholan-24-oic acid, 1/3 ,3a, 7a, 12a tetrahydroxy-cholan-24-oic acid.
  • the polyhydroxylated bile acid according to the present invention is 3a,6a,7a,12a-tetrahydroxy-5 b -cholan-24-oic acid.
  • pharmaceutically acceptable salt refers to a formulation of a bile acid compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the bile acid.
  • Pharmaceutical salts can also be obtained by reacting the compounds of this invention with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a zinc salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl) methylamine, and salts thereof.
  • the pharmaceutically acceptable salt is Na + , K + , Li + , Ca ++ , Mg ++ or Zn ++ .
  • conjugated to refers to compounds, wherein the polyhydroxylated bile acid compound according to the present invention is conjugated to a pharmaceutically acceptable moiety.
  • pharmaceutically acceptable moiety refers to a moiety which provides additional hydrophilicity, charge, function and/or other properties.
  • the pharmaceutically acceptable moiety may after administration optionally be released in clinically acceptable amounts.
  • the polyhydroxylated bile acid according to the present invention is conjugated to a suitable moiety.
  • the polyhydroxylated bile acid is conjugated to an amino acid, e.g., taurine, glycine or serine.
  • the bile acid according to the present invention is conjugated to an acid or a salt thereof, e.g., sulfate, phosphate, etc.; to a sulfonic acid or a salt thereof, e.g., alkyl sulfonate, etc.; organic acid or a thereof, e.g., acetate, lactate, malate, tartrate, citrate, ascorbate, succinate, butyrate, valerate, fumarate, glucuronate, etc.; to a sugar e.g., glucose, or xylose; to an amino sugar e.g., N- acetylglucosamine, glucosamine, or ethanolamine.
  • the pharmaceutically acceptable moiety is taurine, glycine or serine.
  • compositions can also be obtained by reacting a bile acid compound of the invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, succinic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, succinic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • LDL-C Low density lipoprotein cholesterol
  • CVD cardiovascular disease
  • Lp(a) is both a highly prevalent risk factor and the most common monogenetic CVD risk factor.
  • the average levels of Lp(a) differ among different groups and 20-30% population has plasma levels above the risk threshold of about 30 mg/dL (75 nmol/L) for CVD. In Blacks, the average levels of Lp(a) are significantly higher, and in Asians significantly lower. In these groups the cut-off levels where pharmacological treatment is recommended are distinct from Whites. The risk rises nearly linearly with increased Lp(a) levels. Since cholesterol lowering medications in most cases do not reduce Lp(a) levels to a desirable degree it is plausible to combine them with compounds of this invention.
  • the polyhydroxylated bile acid is therefore administered in combination with a cholesterol synthesis inhibitor such as a statin or a cholesterol absorption inhibitor, e.g., Ezetimibe ® .
  • plasma level of lipoprotein (a) refers to the concentration of Lp(a) in plasma given in mg/dL or nmol/L.
  • a subject with an increased plasma level of Lp(a) compared to a desirable reference value plasma level of Lp(a) is treated with a polyhydroxylated bile acid.
  • the desirable reference value of plasma lipoprotein(a) is considered as the value of plasma Lp(a) associated with a no or low cardiovascular risk. Said desirable value may vary regionally worldwide.
  • a concentration of below 15 mg/dl or even of below 10 mg/dl is generally considered as a plasma level of Lp(a) associated with no or low cardiovascular risk.
  • a plasma level of Lp(a) of above 30 mg/dl is considered as increased level associated with an increased risk.
  • a plasma level of Lp(a) of above 60 mg/dl is considered as a condition where a therapeutic intervention is generally recommended by health professionals especially if co-occurring with additional risk factors such as high plasma LDL or low plasma HDL levels.
  • the plasma level of Lp(a) of said subject is decreased by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or at least 60% as compared to the baseline plasma level of Lp(a).
  • the term “baseline” as used herein refers to the subject's lipoprotein (a) level determined prior to or at start of treatment. This baseline is the refence value for determining the effective decrease of the Lp(a) concentration in the subject’s plasma.
  • the Lp(a) level may be determined by enzyme immunoassays (EIAs), by an immunoradiometric assay (IRMA), turbidimetry, nephelometry, liquid chromatography- mass spectroscopy, or by electrophoresis measuring Lp(a)- cholesterol.
  • the present invention provides a pharmaceutical composition for use in the prevention or treatment of a disease associated with an increased plasma level of Lp(a), wherein said pharmaceutical composition comprises a polyhydroxylated bile acid compound and a pharmaceutical acceptable carrier.
  • pharmaceutically acceptable carrier refers to a pharmaceutical carrier according to acceptable pharmaceutical techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • Various organic or inorganic carrier materials conventionally used as materials for pharmaceutical preparations may be used as pharmaceutically acceptable carrier for the compounds of the invention and the route of administration chosen. They are blended as excipient, lubricant, binder or disintegrant for solid preparations; and solvent, solubilizing agent, suspending agent, isotonicity agent, buffer, soothing agent and the like for liquid preparations.
  • an additive for pharmaceutical preparations such as preservative, antioxidant, colorant, sweetening agent and the like can be used.
  • treatment in relation to a given disease or disorder, includes, but is not limited to, inhibiting the disease or disorder, for example, arresting the development of the disease or disorder; relieving the disease or disorder, for example, causing regression of the disease or disorder; or relieving a condition caused by or resulting from the disease or disorder, for example, relieving, preventing or treating symptoms of the disease or disorder.
  • prevention in relation to a given disease or disorder means: preventing the onset of disease development if none had occurred, preventing the disease or disorder from occurring in a subject that may be predisposed to the disorder or disease but has not yet been diagnosed as having the disorder or disease, and/or preventing further disease/disorder development if already present.
  • the present invention relates to the treatment and prevention of a disease associated with an increased plasma level of Lp(a), wherein said associated disease refers to a disease, disorder of condition of a subject having family and/or personal histories of heart disease, lipid metabolism disorder, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, high triglycerides and/or high blood cholesterol levels, non-fatal heart attack, non-fatal stroke, postmenopausal subjects with increased risk factors for heart disease, hypothyroidism, underactive thyroid gland, diabetes, renal disease, renal failure, nephrotic syndrome, hypertension, hemostasis disorders, thrombosis, aortic valve calcification.
  • said associated disease refers to a disease, disorder of condition of a subject having family and/or personal histories of heart disease, lipid metabolism disorder, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, high triglycerides and/or high blood cholesterol levels, non-fatal heart attack, non-fatal stroke, post
  • the disease associated with an increased plasma level of Lp(a) is selected from the group consisting of atherosclerosis; stroke; vascular disease, e.g., cardiovascular disease, peripheral vascular disease, hereditary vascular disease; thrombosis; diabetes; metabolic disease conditions, e.g., dyslipoproteinemia, hyperlipidemia, etc.
  • the disease associated with an increased plasma level of Lp(a) is type II diabetes, hyperlipidemia, or dyslipidemia.
  • Example 1 -3a,6a,7a,12a-tetrahydroxy-5/3-cholan-24-oic acid reduces Apo(a) expression in transgenic Apo(a) mice - in vitro
  • mice generated according to Frazer KA. et al. 1995 (Frazer KA, et al. (1995) Nat Genet. 1995;9(4):424-431) were used.
  • Example 2 - 3a,6a,7a,12a-tetrahydroxy-53 ⁇ 4-cholanoic acid reduces Apo(a) expression in transgenic Apo(a) mice - in vivo
  • mice generated previously (Frazer KA et al. (1995) Nat Genet. 1995;9(4):424-431) were used.
  • THBA 3a,6a,7a,12a-tetrahydroxy-5 b -cholan-24- oic acid (MF: C24H40O6 MW: 424.57) > 95% purity was purchased from UHN Shanghai 88 Cailun Rd, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai, 201210, China. All other chemicals were from Sigma-Aldrich https://www.sigmaaldrich.com if not stated otherwise.
  • RNA expression was measured in primary hepatocytes as well as in whole liver extracts as described previously (Chennamsetty, I., et al. (2011) J. Clin. Invest. 121: 3724 - 3734; Chennamsetty, I., et al. (2012) Arterioscler. Thromb. Vase. Biol. 32: 1220 - 1227; Chennamsetty, I., et al. (2012) J. Lipid Res. 53: 2405-2412).
  • total RNA was extracted using Trizol (Invitrogen) according to the manufacturer’s protocol. Two micrograms of total RNA were reverse transcribed using the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems).
  • Quantitative real-time PCR was performed on a Light Cycler 480 instrument (Roche Diagnostics), using the QuantiFast SYBR Green PCR Kit (Qiagen).
  • the following primer were used: Apo(a) mouse: Forward primer (5’ 3’) GGCACGTATGGCAGCAAGAT (SEQ ID NO:l); Reverse primer (5’ 3’) CCAAGGAGGAGGATTCAAACTG (SEQ ID NO:2); Ppia mouse: Forward primer (5’ 3’) TTCCAGGATTCATGTGCCAG (SEQ ID NO:3); Reverse primer (5’ 3’) CCATCCAGCCATTCAGTCTT (SEQ ID NO:4).
  • Cyp7Al mouse Forward primer (5’ 3’) GGGATTGCTGTGGTAGTGAGC (SEQ ID NO:5); Reverse primer (5’ 3’) GGTATGGAATCAACCCGTTGTC (SEQ ID NO:6).
  • Example 3 - 3a,6a,7a,12a-tetrahydroxy-5/3-cholan-24-oic acid reduces Apo(a) plasma concentrations in transgenic Apo(a) mice - in vivo Results of in vivo experiments:
  • a known FXR agonist is cholic acid (3 a ,7 a ,12 a -trihydroxy-5 b -cholan- 24-oic acid), that in fact reduced plasma Apo(a) concentrations when fed to tg- Apo(a) mice. Due to its unwanted side effects cholic acid is not recommended for use as a medication because it may cause liver damage.

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Abstract

La présente invention concerne un composé d'acide biliaire polyhydroxylé ou un sel pharmaceutiquement acceptable de celui-ci, destiné à être utilisé dans le traitement d'un sujet atteint d'une concentration plasmique accrue de lipoprotéine (a) (Lp(a)).
PCT/EP2021/061679 2021-05-04 2021-05-04 Composés pour réduire la lipoprotéine (a) Ceased WO2022233398A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025221731A1 (fr) * 2024-04-15 2025-10-23 Sage Therapeutics, Inc. Composés modulant le récepteur nmda et leurs procédés d'utilisation

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WO2009105897A1 (fr) 2008-02-26 2009-09-03 British Columbia Cancer Agency Branch Acides biliaires polyhydroxylés destinés au traitement des troubles biliaires
WO2011022838A1 (fr) 2009-08-25 2011-03-03 British Columbia Cancer Agency Branch Acides biliaires polyhydroxylés pour le traitement des troubles biliaires
WO2013041519A1 (fr) 2011-09-19 2013-03-28 ETH Zürich, ETH Transfer Modulateurs de ror gamma
WO2014184271A1 (fr) * 2013-05-14 2014-11-20 Tes Pharma Srl. Dérivés 11-hydroxyle d'acides biliaires et leurs conjugués d'acides aminés en tant que modulateurs du récepteur de farnésoïde x

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Publication number Priority date Publication date Assignee Title
WO2009105897A1 (fr) 2008-02-26 2009-09-03 British Columbia Cancer Agency Branch Acides biliaires polyhydroxylés destinés au traitement des troubles biliaires
WO2011022838A1 (fr) 2009-08-25 2011-03-03 British Columbia Cancer Agency Branch Acides biliaires polyhydroxylés pour le traitement des troubles biliaires
WO2013041519A1 (fr) 2011-09-19 2013-03-28 ETH Zürich, ETH Transfer Modulateurs de ror gamma
WO2014184271A1 (fr) * 2013-05-14 2014-11-20 Tes Pharma Srl. Dérivés 11-hydroxyle d'acides biliaires et leurs conjugués d'acides aminés en tant que modulateurs du récepteur de farnésoïde x

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